Medical practice has for many years prescribed or advised the administration of many biologically active materials for the treatment or prophylaxis of a wide variety of diseases or conditions. One of the most well known, but by no means the only, prescribed biologically active proteinaceous material is insulin, which is used for the control of diabetes.
Possibly the easiest method of taking any medication is oral ingestion. Such route of administration, which may be by means of syrup, elixir, tablets, capsules, granules, powders or any other convenient formulation, is generally simple and straightforward and is frequently the least inconvenient or unpleasant route of administration from the patient's point of view. It is therefore unfortunate, from the point of view of medical treatment and prophylaxis, that the preferred route of administration of proteinaceous medicaments and other biologically active materials involves passing the material through the stomach, which is a hostile environment for many materials, including proteins. As the acidic, hydrolytic and proteolytic environment of the stomach has evolved efficiently to digest proteinaceous materials into amino acids and oligopeptides for subsequent anabolism, it is hardly surprising that very little or any of a wide variety of biologically active proteinaceous material, if simply taken orally, would survive its passage through the stomach to be taken up by the body in the small intestine.
The result, as many diabetics can testify, is that many proteinaceous medicaments have to be taken parenterally, often by subcutaneous, intramuscular or intravenous injection, with all the inconvenience, discomfort and difficulties of patient compliance that that entails.
This is not an isolated problem, as diseases needing control by the administration of proteinaceous material can be very widespread. Diabetes mellitus, for example, claims a large number of sufferers in many countries of the world. Partly because of the large number of patients suffering from diabetes of one form or another, there is a need to develop oral formulations of insulin which are somehow protected against the hostile environment of the stomach. Although various prior attempts at developing such formulations have been made, the applicants are not aware of any prior composition that has to date been commercialised to any appreciable degree. Prior proposals of which the applicants are aware are as follows.
WO-A-8701035 relates to parenterally administrable formulations of fat-soluble drugs and vitamins; the formulations comprise `pseudomicelles`.
WO-A-8705505 discloses orally ingestible compositions of insulin coated onto solid particles from an aqueous preparation; the insulin-coated particles are themselves then coated with lipid.
U.S. Pat. No. 4,849,405 discloses orally ingestible compositions of insulin; the compositions are described as being two-phase preparations, and it appears that both phases are aqueous, with the phases effectively being kept separate by a coacervate system.
EP-A-0140085 discloses drug-containing lipid vesicle preparations.
Shichiri et al (Acta diabet. lat. 15 175-183 (1978)) disclose water-in-oil-in-water insulin micelles.
U.S. Pat. No. 4,784,845 and U.S. Pat. No. 4,816,247 disclose emulsion compositions for the parenteral administration of hydrophobic drugs.
JP-A-55017328 discloses water-in-oil-in-water emulsions containing insulin, for oral ingestion.
EP-A-0366277, published on 2nd May 1990, relates to improved pharmaceutical formulations that can be delivered orally or rectally. More specifically, EP-A-0366277 teaches a pharmaceutical formulation comprising a microemulsion having a hydrophilic phase and a hydrophobic phase, wherein (A) the hydrophilic phase is dispersed in the hydrophobic phase, (B) the hydrophilic phase comprises a biologically active material and (C) the hydrophobic phase contains chylomicra or material from which chylomicra are formed in vivo. The hydrophilic phase can contain a physiologically compatible solvent for the biologically active material, such as water. It is suggested that the biologically active substance, when administered in association with chylomicra or the constituents of chylomicra, is targeted to the villae and microvillae of the intestinal wall, from where it is secreted into the lacteals and intestinal lymph and then drained into the thoracic duct and, ultimately, the circulating bloodstream.
As is known, chylomicra comprise a lipid/cholesteol core or matrix, surrounded by a membrane comprising a phospholipid monolayer which is studded with proteins (Redgrave in Gastrointestinal Physiology IV, International Review of Physiology, Volume 28, 103-130, Young, J. A., Ed., University Park Press, Baltimore, 1983). It can thus be seen that the prior European patent application provides the biologically active material in the hyrophobic core.